Title: Testing Biological Ideas on Evolution, Aging and Longevity with Demographic and Genealogical Data
1Testing Biological Ideas on Evolution, Aging and
Longevity with Demographic and Genealogical Data
- Leonid A. Gavrilov
- Natalia S. Gavrilova
- Center on Aging, NORC/University of Chicago,
- 1155 East 60th Street, Chicago, IL 60637
2What are the data and the predictions of the
evolutionary theory on
- Links between human longevity and fertility
- Lifespan heritability in humans
- Quality of offspring conceived to older parents
3Founding Fathers
- Beeton, M., Yule, G.U., Pearson, K. 1900. Data
for the problem of evolution in man. V. On the
correlation between duration of life and the
number of offspring. Proc. R. Soc. London, 67
159-179. - Data used English Quaker records and Whitney
Family of Connectucut records for females and
American Whitney family and Burkes Landed
Gentry for males.
4Findings and Conclusions by Beeton et al., 1900
- They tested predictions of the Darwinian
evolutionary theory that the fittest individuals
should leave more offspring. - Findings Slightly positive relationship between
postreproductive lifespan (50) of both mothers
and fathers and the number of offspring. - Conclusion fertility is correlated with
longevity even after the fecund period is passed
and selective mortality reduces the numbers of
the offspring of the less fit relatively to the
fitter.
5Other Studies, Which Found Positive Correlation
Between Reproduction and Postreproductive
Longevity
- Telephone inventor Alexander Graham Bell (1918)
- The longer lived parents were the most
fertile. - Bettie Freeman (1935) Weak positive correlations
between the duration of postreproductive life in
women and the number of offspring borne. Human
Biology, 7 392-418. - Bideau A. (1986) Duration of life in women after
age 45 was longer for those women who borne 12 or
more children. Population 41 59-72.
6Studies that Found no Relationship Between
Postreproductive Longevity and Reproduction
- Henry L. 1956. Travaux et Documents.
- Gauter, E. and Henry L. 1958. Travaux et
Documents, 26. - Knodel, J. 1988. Demographic Behavior in the
Past. - Le Bourg et al., 1993. Experimental Gerontology,
28 217-232.
7Study that Found a Trade-Off Between
Reproductive Success and Postreproductive
Longevity
- Westendorp RGJ, Kirkwood TBL. 1998. Human
longevity at the cost of reproductive success.
Nature 396 743-746. - Extensive media coverage including BBC and over
100 citations in scientific literature as an
established scientific fact. Previous studies
were not quoted and discussed in this article.
8Point estimates of progeny number for married
aristocratic women from different birth cohorts
as a function of age at death. The estimates of
progeny number are adjusted for trends over
calendar time using multiple regression.
- Source Westendorp, Kirkwood, Human longevity at
the cost of reproductive success. Nature, 1998,
396, pp 743-746
9Number of progeny and age at first childbirth
dependent on the age at death of married
aristocratic women
- Source Westendorp, R. G. J., Kirkwood, T. B. L.
Human longevity at the cost of reproductive
success. Nature, 1998, 396, pp 743-746
10 it is not a matter of reduced fertility, but a
case of 'to have or have not'.
Source Toon Ligtenberg Henk Brand. Longevity
does family size matter? Nature, 1998, 396, pp
743-746
11- Source Westendorp, R. G. J., Kirkwood, T. B. L.
Human longevity at the cost of reproductive
success. Nature, 1998, 396, pp 743-746
12Do longevous women have impaired fertility ?Why
is this question so important and interesting?
Scientific Significance
- This is a testable prediction of some
evolutionary theories of aging - disposable soma
theory of aging (Kirkwood)
"The disposable soma theory on the evolution of
ageing states that longevity requires investments
in somatic maintenance that reduce the resources
available for reproduction (Westendorp,
Kirkwood, Nature, 1998).
13Do longevous women have impaired fertility ?
- Practical Importance.
- Do we really wish to live a long life at the
cost of infertility? -
- the next generations of Homo sapiens will
have even longer life spans but at the cost of
impaired fertility - Rudi Westendorp Are we becoming less
disposable? EMBO Reports, 2004, 5 2-6.
"... increasing longevity through genetic
manipulation of the mechanisms of aging raises
deep biological and moral questions. These
questions should give us pause before we embark
on the enterprise of extending our lives
Walter Glennon "Extending the Human Life Span",
Journal of Medicine and Philosophy, 2002, Vol.
27, No. 3, pp. 339-354.
14- Educational Significance
- Do we teach our students right?
- Impaired fertility of longevous women is
often presented in scientific literature and mass
media as already established fact (Brandt et al.,
2005 Fessler et al., 2005 Schrempf et al.,
2005 Tavecchia et al., 2005 Kirkwood, 2002
Westendorp, 2002, 2004 Glennon, 2002 Perls et
al., 2002 etc.). - This "fact" is now included in teaching
curriculums in biology, ecology and anthropology
world-wide (USA, UK, Denmark). -
- Is it a fact or artifact ?
15General Methodological Principle
- Before making strong conclusions, consider all
other possible explanations, including potential
flaws in data quality and analysis - Previous analysis by Westendorp and Kirkwood was
made on the assumption of data completenessNumbe
r of children born Number of children
recorded - Potential concerns data incompleteness,
under-reporting of short-lived children, women
(because of patrilineal structure of genealogical
records), persons who did not marry or did not
have children.Number of children born gtgt
Number of children recorded
16Test for Data Completeness
- Direct Test Cross-checking of the initial
dataset with other data sources - We examined 335 claims of childlessness in
the dataset used by Westendorp and Kirkwood.
When we cross-checked these claims with other
professional sources of data, we found that at
least 107 allegedly childless women (32) did
have children! - At least 32 of childlessness claims proved to
be wrong ("false negative claims") ! - Some illustrative examples
- Henrietta Kerr (16531741) was apparently
childless in the dataset used by Westendorp and
Kirkwood and lived 88 years. Our cross-checking
revealed that she did have at least one child,
Sir William Scott (2nd Baronet of Thirlstane,
died on October 8, 1725). - Charlotte Primrose (17761864) was also
considered childless in the initial dataset and
lived 88 years. Our cross-checking of the data
revealed that in fact she had as many as five
children Charlotte (18031886), Henry
(18061889), Charles (18071882), Arabella
(1809-1884), and William (18151881). - Wilhelmina Louise von Anhalt-Bernburg
(17991882), apparently childless, lived 83
years. In reality, however, she had at least
two children, Alexander (18201896) and Georg
(18261902).
17Point estimates of progeny number for married
aristocratic women from different birth cohorts
as a function of age at death. The estimates of
progeny number are adjusted for trends over
calendar time using multiple regression.
- Source Westendorp, R. G. J., Kirkwood, T. B. L.
Human longevity at the cost of reproductive
success. Nature, 1998, 396, pp 743-746
18Antoinette de Bourbon(1493-1583)
- Lived almost 90 years
- She was claimed to have only one child in the
dataset used by Westendorp and Kirkwood Marie
(1515-1560), who became a mother of famous Queen
of Scotland, Mary Stuart. - Our data cross-checking revealed that in fact
Antoinette had 12 children! - Marie 1515-1560
- Francois Ier 1519-1563
- Louise 1521-1542
- Renee 1522-1602
- Charles 1524-1574
- Claude 1526-1573
- Louis 1527-1579
- Philippe 1529-1529
- Pierre 1529
- Antoinette 1531-1561
- Francois 1534-1563
- Rene 1536-1566
19Characteristics of Our Data Sample for
Reproduction-Longevity Studies
- 3,723 married women born in 1500-1875 and
belonging to the upper European nobility. - Women with two or more marriages (5) were
excluded from the analysis in order to facilitate
the interpretation of results (continuity of
exposure to childbearing).
- Every case of childlessness has been checked
using at least two different genealogical
sources.
20Typical Mistakes in Biological Studies of Human
Longevity
- Using lifespan data for non-extinct birth cohorts
(cemetery effect) - Failure to control for birth cohort spurious
correlations may be found if variables have
temporal dynamics - Failure to take into account social events and
factors e.g., failure to control for age at
marriage in longevity-reproduction studies
21Childlessness is better outcome than number of
children for testing evolutionary theories of
aging on human data
- Applicable even for population practicing birth
control (few couple are voluntarily childless) - Lifespan is not affected by physiological load of
multiple pregnancies - Lifespan is not affected by economic hardship
experienced by large families
22(No Transcript)
23Source Gavrilova et al. Does exceptional human
longevity come with high cost of infertility?
Testing the evolutionary theories of aging.
Annals of the New York Academy of Sciences, 2004,
1019 513-517.
24Source Gavrilova, Gavrilov. Human longevity and
reproduction An evolutionary perspective. In
Grandmotherhood - The Evolutionary Significance
of the Second Half of Female Life. Rutgers
University Press, 2005 (in press).
25Short Conclusion
- Exceptional human longevity is NOT associated
with infertility or childlessness
26More Detailed Conclusions
- We have found that previously reported high rate
of childlessness among long-lived women is an
artifact of data incompleteness, caused by
under-reporting of children. After data cleaning,
cross-checking and supplementation the
association between exceptional longevity and
childlessness has disappeared. - Thus, it is important now to revise a highly
publicized scientific concept of heavy
reproductive costs for human longevity. and to
make corrections in related teaching curriculums
for students. - It is also important to disavow the doubts and
concerns over further extension of human
lifespan, that were recently cast in biomedical
ethics because of gullible acceptance of the idea
of harmful side effects of lifespan extension,
including infertility (Glannon, 2002). - There is little doubt that the number of children
can affect human longevity through complications
of pregnancies and childbearing, as well as
through changes in socioeconomic status, etc.
However, the concept of heavy infertility cost
of human longevity is not supported by data, when
these data are carefully reanalyzed.
27Mutation Accumulation Theory of Aging (Medawar,
1946)
- From the evolutionary perspective, aging is an
inevitable result of the declining force of
natural selection with age. - So, over successive generations, late-acting
deleterious mutations will accumulate, leading to
an increase in mortality rates late in life.
28Predictions of the Mutation Accumulation Theory
of Aging
- Mutation accumulation theory predicts that those
deleterious mutations that are expressed in later
life should have higher frequencies (because
mutation-selection balance is shifted to higher
equilibrium frequencies due to smaller selection
pressure). - Therefore, expressed genetic variability should
increase with age (Charlesworth, 1994. Evolution
in Age-structured Populations). - This should result in higher heritability
estimates for lifespan of offspring born to
longer-lived parents.
29Linearity Principle of Inheritance in
Quantitative Genetics
- Dependence between parental traits and offspring
traits is linear
30The Best Possible Source on Familial Longevity
Genealogies of European Royal and Noble Families
Marie-Antoinette von Habsburg-Lothringen
(1765-1793)
Charles IX dAnguleme (1550-1574)
Henry VIII Tudor (1491-1547)
31Characteristic of our Dataset
- Over 16,000 persons belonging to the European
aristocracy - 1800-1880 extinct birth cohorts
- Adult persons aged 30
- Data extracted from the professional genealogical
data sources including Genealogisches Handbook
des Adels, Almanac de Gotha, Burke Peerage and
Baronetage.
32Daughter's Lifespan(Mean Deviation from Cohort
Life Expectancy)as a Function of Paternal
Lifespan
- Offspring data for adult lifespan (30 years) are
smoothed by 5-year running average. - Extinct birth cohorts (born in 1800-1880)
- European aristocratic families. 6,443
cases
33The Heritability of Life-Spans Is SmallC.E.
Finch, R.E. Tanzi, Science, 1997, p.407
Paradox of low heritability of lifespan vs high
familial clustering of longevity
long life runs in families A. Cournil, T.B.L.
Kirkwood, Trends in Genetics, 2001, p.233
34Heritability Estimates of Human Lifespan
35Is the effect of non-linear inheritance remain
valid after controlling for other explanatory
variables?
- Lifespan of other parent
- Parental ages at childs conception
- Ethnicity
- Month of birth
36Offspring Lifespan at Age 30 as a Function
of Paternal LifespanData are adjusted for
other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases
37Offspring Lifespan at Age 30 as a Function
of Maternal LifespanData are adjusted for
other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases
38Is the effect of non-linear inheritance observed
for non-biological relatives?
- We need to test an alternative hypothesis that
positive effects of long-lived parents on the
offspring survival may be non-biological and
caused by common environment and life style - What about lifespan of spouses?
39Persons Lifespan as a Function of Spouse
LifespanData are adjusted for other predictor
variables
Married Women, 4,530 cases
Married Men, 5,102 cases
40What about lifespan of other relatives?
(sisters vs sisters-in-law)
41Persons Lifespan as a Function of Sisters
LifespanData are adjusted for other predictor
variables
Females, 5,421 cases
Males, 7,378 cases
42Persons Lifespan as a Function of
Sisters-In-Law LifespanData are adjusted for
other predictor variables
Females, 4,789 cases
Males, 4,707 cases
43Mortality Kinetics for Progeny Born to Long-Lived
(80) vs Short-Lived Parents Data are adjusted
for historical changes in lifespan
Sons
Daughters
44Parental-Age Effects in Humans (accumulation of
mutation load in parental germ cells)
- What are the Data and the Predictions of
Evolutionary Theory on the Quality of Offspring
Conceived to Older Parents? - Does progeny conceived to older parents live
shorter lives?
45Evolutionary Justification for Parental-Age
Effects
- "The evolutionary explanation of senescence
proposes that selection against alleles with
deleterious effects manifested only late in life
is weak because most individuals die earlier for
extrinsic reasons. - This argument also applies to alleles whose
deleterious effects are nongenetically
transmitted from mother to progeny, that is, that
affect the performance of progeny produced at
late ages rather than of the aging individuals
themselves. - a decline of offspring quality with parental
age should receive more attention in the context
of the evolution of aging. - Stearns et al. "Decline in offspring
viability as a manifestation of aging in
Drosophila melianogaster." Evolution, 2001, Vol.
55, No. 9, pp. 18221831.
46Genetic Justification for Paternal Age Effects
- Advanced paternal age at child conception is the
main source of new mutations in human
populations. - James F. Crow
47Paternal Age and Risk of Schizophrenia
- Estimated cumulative incidence and percentage of
offspring estimated to have an onset of
schizophrenia by age 34 years, for categories of
paternal age. The numbers above the bars show the
proportion of offspring who were estimated to
have an onset of schizophrenia by 34 years of
age. - Source Malaspina et al., Arch Gen
Psychiatry.2001.
48Paternal Age as a Risk Factor for Alzheimer
Disease
- MGAD - major gene for Alzheimer Disease
- Source L. Bertram et al. Neurogenetics, 1998, 1
277-280.
49Daughters' Lifespan (30) as a Functionof
Paternal Age at Daughter's Birth6,032 daughters
from European aristocratic families born in
1800-1880
- Life expectancy of adult women (30) as a
function of father's age when these women were
born (expressed as a difference from the
reference level for those born to fathers of
40-44 years). - The data are point estimates (with standard
errors) of the differential intercept
coefficients adjusted for other explanatory
variables using multiple regression with nominal
variables. - Daughters of parents who survived to 50
years.
50Contour plot for daughters lifespan (deviation
from cohort mean) as a function of paternal
lifespan (X axis) and paternal age at daughters
birth (Y axis)
7984 cases 1800-1880 birth cohorts European
aristocratic families Distance weighted least
squares smooth
51Daughters Lifespan as a Function of
Paternal Age at Daughters Birth Data are
adjusted for other predictor variables
Daughters of shorter-lived fathers (lt80), 6727
cases
Daughters of longer-lived fathers (80), 1349
cases
52Conclusions
- Being conceived to old fathers is a risk factor,
but it is modulated by paternal longevity - It is OK to be conceived to old father if he
lives more than 80 years
53Acknowledgments
- This study was made possible thanks to
- generous support from the National Institute on
Aging, and - stimulating working environment at the Center
on Aging, NORC/University of Chicago
54For More Information and Updates Please Visit Our
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